Emulsion eye drops

Abstract

The present invention provides an emulsion eye drop that has no corneal obstruction caused by nonionic surfactants, has excellent thermal stability and physical stability, and can increase the content of a poorly water-soluble drug, as well as a method for stabilizing the emulsion eye drop. The emulsion eye drop contains castor oil and polyvinyl alcohol, wherein the concentration of castor oil is 5 to 20 w / v%, the concentration of polyvinyl alcohol is 2 to 7 w / v%, and the weight ratio of castor oil to polyvinyl alcohol is 1.2 to 5. In addition, the method for stabilizing the emulsion eye drop is characterized by preparing the emulsion eye drop, wherein the emulsion eye drop contains castor oil and polyvinyl alcohol, wherein the concentration of castor oil is 5 to 20 w / v%, the concentration of polyvinyl alcohol is 2 to 7 w / v%, and the weight ratio of castor oil to polyvinyl alcohol is 1.2 to 5.

Description

Technical Field

[0001] The present invention generally relates to emulsion eye drops, and particularly relates to oil-in-water emulsion eye drops. Background Art

[0002] In the past, as eye drops containing poorly water-soluble drugs, there are emulsion eye drops. As emulsifiers for emulsion eye drops, generally speaking, nonionic surfactants are used. For example, in Japanese Patent Application Laid-Open No. 11-029483 (Patent Document 1), a kind of emulsified composition is recorded, which comprises difluprednate as a poorly water-soluble drug, castor oil as oil, water, and nonionic surfactant polysorbate as an emulsifier.

[0003] In addition, International Publication No. WO2009 / 063692 (Patent Document 2) describes a drug-containing fat emulsion comprising at least a poorly water-soluble drug, oil, emulsifier, and water as constituent components, characterized in that the oil content is 0.05 to 2 mg / mL, the weight ratio of the drug to the oil (drug / oil) is 0.01 to 20 (wherein the maximum total content of the drug and oil is 5 mg / mL), and the weight ratio of the emulsifier to the oil (emulsifier / oil) is 1 to 300.

[0004] International Publication No. WO2005 / 044276 (Patent Document 3) describes a method for preparing a prostaglandin F-containing 2α Eye drops of oil-in-water emulsions of derivatives, oils, water-soluble polymers and water.

[0005] Prior art literature

[0006] Patent Literature

[0007] Patent Document 1: Japanese Patent Application Laid-Open No. 11-029483

[0008] Patent Document 2: International Publication No. WO2009 / 063692

[0009] Patent Document 3: International Publication No. WO2005 / 044276 Summary of the Invention

[0010] Problems to be solved by the invention

[0011] Nonionic surfactants are highly irritating to the ocular mucosa. If a composition containing a high concentration of a nonionic surfactant as an emulsifier is used as an eye drop, corneal damage caused by the nonionic surfactant may occur.

[0012] Furthermore, as in the drug-containing fat emulsion of Patent Document 2, if the content of the oil component is less than the content of the emulsifier, there arises a problem that the content of the poorly water-soluble drug cannot be increased.

[0013] In addition, Patent Document 3 discloses an emulsion eye drop solution that combines a medium-chain fatty acid triglyceride and a water-soluble polymer as an emulsifier. However, if the oil content is greater than the emulsifier content, the inclusion of a nonionic surfactant as an emulsifier may cause corneal obstruction caused by the nonionic surfactant. On the other hand, if the nonionic surfactant is not included, the oil content is less than the emulsifier content. In this case, as in Patent Document 2, the content of the poorly water-soluble drug cannot be increased. In addition, while the stability of the drug to heating is taken into consideration, the stability of the emulsion itself is not taken into consideration.

[0014] Eye drops, whether aqueous or emulsion, are typically sterilized by filtration. However, those that cannot be sterilized by filtration are sterilized by heat. However, since emulsion compositions are generally unstable to heat, heat-sterilized emulsion eye drops require exceptionally high thermal stability, where the particle size does not change with heating. Furthermore, since emulsion eye drops are formulated to minimize particle size changes with long-term storage, they require excellent thermal and physical stability.

[0015] Therefore, an object of the present invention is to provide an emulsion eye drop that has a low risk of onset of corneal disorders, is excellent in thermal stability and physical stability, and can increase the content of a poorly water-soluble drug.

[0016] Methods for solving problems

[0017] The present inventors conducted intensive research to address the above-mentioned issues. As a result, they discovered that all of the above-mentioned issues can be addressed for the first time by providing an emulsion eye drop containing castor oil and polyvinyl alcohol, with the castor oil concentration being 5 to 20 w / v%, the polyvinyl alcohol concentration being 2 to 7 w / v%, and the castor oil to polyvinyl alcohol weight ratio (hereinafter sometimes referred to as "C / P") being 1.2 to 5.

[0018] Based on the above findings, the emulsion eye drops of the present invention are formulated as follows.

[0019] [1] An emulsion eye drop comprising castor oil and polyvinyl alcohol, wherein the concentration of castor oil is 5 to 20 w / v%, the concentration of polyvinyl alcohol is 2 to 7 w / v%, and the weight ratio of castor oil to polyvinyl alcohol is 1.2 to 5.

[0020] [2] The emulsion eye drops according to [1] above, which do not substantially contain a nonionic surfactant.

[0021] [3] The emulsion eye drops according to [1] or [2] above, further comprising a poorly water-soluble drug.

[0022] [4] The emulsion eye drops according to any one of [1] to [3] above, wherein when the emulsion eye drops are sterilized by autoclave at 121°C for 20 minutes, the change rate of the average particle size of oil droplets contained in the emulsion eye drops before and after autoclave sterilization is less than 3%.

[0023] [5] The emulsion eye drops according to [4] above, wherein the average particle size of the oil droplets contained in the emulsion eye drops of the present invention before the autoclave sterilization is 100 to 200 nm.

[0024] [6] The emulsion eye drops according to any one of [1] to [5] above, wherein the emulsion eye drops are homogeneous when the emulsion eye drops are centrifuged at 20,000×g for 20 minutes.

[0025] [7] A method for stabilizing an emulsion eye drop, comprising the step of preparing the following emulsion eye drops, wherein the emulsion eye drops contain castor oil and polyvinyl alcohol, wherein the concentration of castor oil is 5 to 20 w / v%, the concentration of polyvinyl alcohol is 2 to 7 w / v%, and the weight ratio of castor oil to polyvinyl alcohol is 1.2 to 5.

[0026] [8] The method for stabilizing an emulsion eye drop according to [7] above, wherein the emulsion eye drop does not substantially contain a nonionic surfactant.

[0027] [9] The stabilization method according to [7] or [8] above, wherein the emulsion eye drops further contain a poorly water-soluble drug.

[0028]

[10] According to the stabilization method described in any one of [7] to [9] above, when the emulsion eye drops are sterilized by autoclave at 121°C for 20 minutes, the change rate of the average particle size of the oil droplets contained in the emulsion eye drops before and after autoclave sterilization is less than 3%.

[0029]

[11] According to the stabilization method described in

[10] above, the average particle size of the oil droplets contained in the emulsion eye drops before autoclave sterilization is 100 to 200 nm.

[0030]

[12] The stabilization method according to any one of [7] to

[11] above, wherein the emulsion eye drops are homogeneous when the emulsion eye drops are centrifuged at 20,000×g for 20 minutes.

[0031] Effects of the Invention

[0032] As described above, according to the present invention, since the emulsion eye drops of the present invention do not contain a nonionic surfactant, an emulsion eye drop with a reduced risk of corneal disorders can be provided. In addition, since the emulsion eye drops of the present invention have extremely small changes in particle size even when autoclaved, the present invention can provide an emulsion eye drop that can be autoclaved. In addition, the eye drops of the present invention maintain a stable particle size even under thermally harsh conditions such as autoclave sterilization, and do not cream even under conditions where a gravity load is applied by centrifugation. Therefore, according to the present invention, a stable emulsion eye drop can be provided whose properties do not change even when stored for a long time. In addition, regarding the stabilization method of the emulsion eye drop of the present invention, the emulsion eye drop maintains a stable particle size even under thermally harsh conditions such as autoclave sterilization, does not cream even under conditions where a gravity load is applied by centrifugation, and does not change its properties even when stored for a long time, and can be stabilized. DETAILED DESCRIPTION

[0033] Hereinafter, embodiments of the present invention will be described.

[0034] The emulsion eye drops of the present invention contain 5 to 20 w / v% castor oil and 2 to 7 w / v% polyvinyl alcohol, more preferably 5 to 10 w / v% castor oil and 2 to 4 w / v% polyvinyl alcohol, with the weight ratio of castor oil to polyvinyl alcohol being 1.2 to 5. In the emulsion eye drops of the present invention, the weight ratio of castor oil to polyvinyl alcohol is preferably 2.5 to 5. In addition, the emulsion eye drops of the present invention preferably do not substantially contain a nonionic surfactant. The so-called emulsion eye drops in the present invention are eye drops in which castor oil is emulsified with polyvinyl alcohol and exists as fine oil droplets uniformly dispersed in an aqueous solution to form an oil-in-water emulsion.

[0035] By doing so, it is possible to provide an emulsion eye drop solution with a reduced risk of corneal disorders, an emulsion eye drop solution with excellent thermal and physical stability, and an emulsion eye drop solution capable of increasing the content of a poorly water-soluble drug.

[0036] If any one of the types, contents, and content ratios of the oil component and the emulsifier is outside the scope of the present invention, the above-mentioned problems cannot be solved.

[0037] Furthermore, the emulsion eye drops of the present invention preferably contain a poorly water-soluble drug.

[0038] Furthermore, the emulsion eye drops of the present invention preferably have a change rate of less than 3% in the average particle size of oil droplets contained in the emulsion eye drops before and after autoclave sterilization when the emulsion eye drops are autoclaved at 121° C. for 20 minutes, particularly preferably less than 2%, and even more preferably less than 1%.

[0039] Furthermore, it is preferred that the average particle size of the oil droplets contained in the emulsion eye drops of the present invention before the above-mentioned autoclave sterilization is 100 to 200 nm.

[0040] By doing so, the emulsion eye drops can be filtered using a filter for the purpose of removing foreign matter during the production process.

[0041] Furthermore, the emulsion eye drops of the present invention preferably have fine oil droplets uniformly dispersed when the emulsion eye drops are centrifuged at 20,000×g at 25° C. for 20 minutes.

[0042] castor oil

[0043] The castor oil used in the present invention is not particularly limited as long as it is pharmacologically or physiologically acceptable. Castor oil obtained from seeds by a known extraction method or a known purification method, or commercially available castor oil can be used. However, castor oil that conforms to the 17th revised edition of the Japanese Pharmacopoeia is preferred.

[0044] polyvinyl alcohol

[0045] The viscosity of the polyvinyl alcohol used in the present invention (4 w / w% solution) is not particularly limited, and polyvinyl alcohol generally used in the field of ophthalmology can be used, typically 2 to 100 mm 2 / s. The viscosity of polyvinyl alcohol (4 w / w% solution) is the value measured at 20±0.1°C by cooling a solution of polyvinyl alcohol dissolved in purified water to a 4 w / w% concentration at 60-80°C using a capillary viscometer (Viscometry Method 1, 17th Revised Edition of the Japanese Pharmacopoeia). The polyvinyl alcohol used in the present invention may be a completely saponified product or a partially saponified product.

[0046] Nonionic surfactants

[0047] The phrase "substantially containing no nonionic surfactant" in the present invention means that no nonionic surfactant is added or an amount of the nonionic surfactant is added such that the emulsification effect of the nonionic surfactant cannot be fully exhibited.

[0048] A nonionic surfactant is a surfactant that does not exhibit ionicity in solution but has surface activity and forms micelles in solution. Examples of nonionic surfactants include polyoxyethylene hydrogenated castor oils or polyoxyethylene sorbitan fatty acid esters, preferably polyoxyethylene sorbitan monooleates (e.g., polysorbate 80), polyoxyethylene sorbitan monolaurates, polyoxyethylene sorbitan monopalmitates, and polyoxyethylene sorbitan monostearates.

[0049] Poorly water-soluble drugs

[0050] As used herein, poorly water-soluble drugs refer to drugs for which the volume of purified water required to dissolve 1 g of the drug at 25°C and 1 atm is generally 1000 ml or more, preferably 10,000 ml or more, and more preferably 100,000 ml or more. Specifically, poorly water-soluble drugs are drugs corresponding to the solubility terms "extremely poorly soluble" and "almost insoluble" in the Japanese Pharmacopoeia (17th Revised Edition of the Japanese Pharmacopoeia, General Principle A-13, Hirokawa Shoten, 2016).

[0051] The poorly water-soluble drug is not particularly limited and can be appropriately selected from steroidal anti-inflammatory agents, nonsteroidal anti-inflammatory agents, antihistamines, antiallergic agents, antibacterial agents, etc., depending on the intended use. Among such poorly water-soluble drugs, examples of steroidal anti-inflammatory agents include loteprednol etabonate, fluorometholone, hydrocortisone, betamethasone, beclomethasone dipropionate, and fluticasone propionate.

[0052] The poorly water-soluble drug is present in the oil droplets (in the oil phase) in the emulsion eye drops of the present invention. The content (concentration) of the poorly water-soluble drug is not particularly limited as long as it does not affect the properties of the emulsion. The emulsion eye drops of the present invention can contain the poorly water-soluble drug up to a concentration equivalent to the saturated solubility of the poorly water-soluble drug in castor oil. The specific concentration of the poorly water-soluble drug varies depending on the poorly water-soluble drug contained and the target disease, but is generally 0.001% to 2%, preferably 0.01% to 1%, and more preferably 0.1% to 0.5%.

[0053] Other additives

[0054] Furthermore, the emulsion eye drops of the present invention may contain additives commonly used in eye drops as needed. Specific examples of such additives include buffers, isotonicity agents, solubilizers, viscosity bases, chelating agents, cooling agents, pH adjusters, preservatives, stabilizers, and the like.

[0055] Examples of the buffer include phosphate buffer, boric acid buffer, citric acid buffer, tartaric acid buffer, acetic acid buffer, Tris buffer, and amino acids.

[0056] Examples of the isotonicity agent include sugars such as sorbitol, glucose, and mannitol; polyols such as glycerol and propylene glycol; salts such as sodium chloride; and boric acid.

[0057] Examples of the solubilizing agent include polyols such as glycerin and polyethylene glycol (Macrogol).

[0058] Examples of the viscous base include water-soluble polymers such as polyvinyl pyrrolidone, polyethylene glycol, and carboxyvinyl polymer; and celluloses such as hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose.

[0059] Examples of the chelating agent include sodium edetate and citric acid.

[0060] Examples of the cooling agent include l-menthol, borneol, camphor, and eucalyptus oil.

[0061] Examples of the pH adjuster include bases such as sodium hydroxide and potassium hydroxide; and acids such as acetic acid, citric acid, hydrochloric acid, phosphoric acid, and tartaric acid.

[0062] Examples of preservatives include sorbic acid, potassium sorbate, sodium benzoate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, chlorhexidine gluconate, boric acid, dehydroacetic acid, sodium dehydroacetate, benzethonium chloride, benzyl alcohol, zinc chloride, parachloro-m-xylenol, chlorocresol, phenethyl alcohol, polychloridium chloride, thimerosal, and sodium chlorite.

[0063] Examples of the stabilizer include polyvinyl pyrrolidone, sodium sulfite, monoethanolamine, glycerin, propylene glycol, cyclodextrin, dextran, ascorbic acid, sodium edetate, taurine, and tocopherol.

[0064] pH / Osmolality Ratio

[0065] The pH and osmotic pressure of the emulsion eye drops of the present invention are not particularly limited, as long as they are within the acceptable range for eye drops. Specifically, the pH of the emulsion eye drops of the present invention is about 3 to 9, preferably about 4 to 8. Furthermore, the osmotic pressure of the emulsion eye drops of the present invention is about 0.5 to 3, preferably about 0.9 to 1.1, as a ratio of the osmotic pressure to that of the Japanese Pharmacopoeia physiological saline solution.

[0066] Traits

[0067] The emulsion eye drops of the present invention are castor oil emulsified with polyvinyl alcohol and uniformly dispersed as fine oil droplets in an aqueous solution to form an oil-in-water emulsion.

[0068] The average particle size of the oil droplets of the emulsion eye drops of the present invention before autoclave sterilization is preferably 50 to 500 nm, more preferably 100 to 200 nm, and particularly preferably 130 to 180 nm. The average particle size can be measured using a particle size analyzer (dynamic light scattering method).

[0069] Manufacturing method

[0070] The emulsion eye drops of the present invention can be prepared using known methods. For example, castor oil, polyvinyl alcohol, any additives, and water, which have dissolved a poorly water-soluble drug, can be mixed and emulsified to prepare the emulsion eye drops of the present invention. To achieve uniform emulsification, known methods such as a homogenizer, homogenizer, microfluidizer, and high-pressure homogenizer can be used. The components of the emulsion eye drops of the present invention can be added in any order.

[0071] Stabilization method

[0072] The present invention also relates to a method for stabilizing emulsion eye drops. The method comprises preparing the emulsion eye drops, wherein the emulsion eye drops contain castor oil and polyvinyl alcohol, wherein the castor oil concentration is 5-20 w / v%, the polyvinyl alcohol concentration is 2-7 w / v%, and the weight ratio of castor oil to polyvinyl alcohol is 1.2-5. In this stabilization method, the castor oil content is preferably 5-10 w / v%, the polyvinyl alcohol content is preferably 2-4 w / v%, and the weight ratio of castor oil to polyvinyl alcohol is preferably 2.5-5. More preferably, substantially no nonionic surfactant is contained in the stabilization method. In this stabilization method, the order or method of mixing castor oil, polyvinyl alcohol, water, and any other optional additives is not particularly limited, as long as the stabilization effect is achieved.

[0073] In the present invention, stabilization means that the emulsion eye drops maintain a stable particle size even under thermally harsh conditions such as autoclave sterilization and do not cream even under conditions where a gravity load is applied by centrifugation.

[0074] Furthermore, in the stabilization method of the present invention, when the emulsion eye drops are autoclaved at 121° C. for 20 minutes, the change rate of the average particle size of oil droplets contained in the emulsion eye drops before and after autoclaving is preferably less than 3%.

[0075] Furthermore, in the stabilization method of the present invention, it is preferred that the average particle size of the oil droplets contained in the emulsion eye drops before autoclave sterilization is 100 to 200 nm.

[0076] Furthermore, in the stabilization method of the present invention, it is preferred that when the emulsion eye drops are centrifuged at 20,000×g for 20 minutes, fine oil droplets in the emulsion eye drops are uniformly dispersed.

[0077] Furthermore, in the stabilization method of the present invention, it is preferred that the emulsion eye drops further contain a poorly water-soluble drug.

[0078] In the stabilization method of the present invention, the preparation method of the emulsion eye drops is not particularly limited. As an example, the emulsion eye drops can be prepared according to the above-mentioned method for preparing the emulsion eye drops. In addition, for example, the emulsion eye drops can be prepared according to the method described in Test Example 1 (1-1) described below.

[0079] The stabilization method of the present invention may include a step for confirming stabilization. For example, the method may include a step for measuring the particle size before autoclave sterilization, a step for measuring the particle size after autoclave sterilization, a step for calculating the rate of change in particle size due to autoclave sterilization, and a step for observing changes in properties after centrifugation. These steps can be performed, for example, according to Test Example 1 (1-2) (1-3) described below.

[0080] Example

[0081] Hereinafter, examples of the present invention will be described. The content (%) of each component is w / v% unless otherwise specified.

[0082] (Test Example 1)

[0083] (1-1) Preparation of emulsion and confirmation of properties

[0084] According to the formulations shown in Tables 1 to 5, each water-soluble polymer, concentrated glycerin, and sodium acetate hydrate were added to purified water and dissolved to prepare an aqueous phase. Castor oil was added to the aqueous phase while stirring it with a TK RoboMix (manufactured by Premium Mix) (70°C, 8000 rpm, 15 minutes) to obtain a crude emulsion. The properties of these crude emulsions were evaluated as "AA" if they were completely emulsified, "A" if they had slight oil droplets floating on the surface but were emulsified, "B" if they had oil spread on the surface but were slightly emulsified, and "F" if they were not emulsified. Furthermore, the materials evaluated as "AA" and "A" were micronized using a Starburst (wet micronizer, manufactured by Suginomashin Co., Ltd.) (240 MPa, 20 passes) and the pH was adjusted to 5.5 using hydrochloric acid or sodium hydroxide to obtain oil-in-water emulsions.

[0085] (1-2) Particle size changes caused by autoclave sterilization (AC sterilization)

[0086] An oil-in-water emulsion filled in a glass ampoule was autoclaved (at 121°C for 20 minutes). The average particle size (hereinafter referred to as "particle size") of the oil droplets contained in the oil-in-water emulsion was measured before and after autoclaving using a Zeta Sizernano ZS (ZEN3600 manufactured by Maruvan). A liquid prepared by diluting the oil-in-water emulsion 100-fold with purified water was used as a sample for particle size measurement. A change in particle size before and after autoclaving of less than 3% was rated "A," a change of 3% or more to less than 5% was rated "B," and a change of 5% or more was rated "F." The results are shown in Tables 1 to 5.

[0087] AC particle size change rate before and after sterilization (%) =

[0088] |AC particle size after sterilization - AC particle size before sterilization| / AC particle size before sterilization × 100

[0089] (1-3) Changes in properties relative to centrifugal

[0090] The oil-in-water emulsion was centrifuged at 13,000 rpm (approximately 20,000 × g) for 20 minutes at 25°C, and its properties were observed. A homogeneous solution was rated "A," a solution with shallow depths was rated "B," and a solution with visible emulsion phase separation was rated "F." The results are shown in Tables 1 to 5.

[0091] [Table 1]

[0092]

[0093] [Table 2]

[0094]

[0095] [Table 3]

[0096]

[0097] [Table 4]

[0098]

[0099] [Table 5]

[0100]

[0101] As shown in Tables 1 to 5, crude emulsions containing 1 to 8% polyvinyl alcohol and 4 to 8% hypromellose (TC-5E) or 2 to 4% hypromellose (60SH-50) exhibited favorable properties. Furthermore, when the crude emulsions exhibiting favorable properties were micronized and the changes in particle size due to autoclave sterilization (AC sterilization) and changes in properties following centrifugation were evaluated, the emulsions containing 2 to 4% polyvinyl alcohol exhibited favorable results. This demonstrates that, among formulations containing 5% castor oil, only the formulation containing 2 to 4% polyvinyl alcohol as a water-soluble polymer produced a stable oil-in-water emulsion.

[0102] (Test Example 2)

[0103] Oil-in-water emulsions were prepared according to the formulations shown in Tables 6 to 8. The preparation method was the same as in Test Example 1 (1-1). The properties of the crude emulsified emulsions were all "AA." The micronized oil-in-water emulsions were evaluated for changes in particle size due to autoclave sterilization (AC sterilization) and changes in properties relative to centrifugation using the methods of Test Examples 1 (1-2) and (1-3). The results are shown in Tables 6 to 8.

[0104] [Table 6]

[0105]

[0106] [Table 7]

[0107]

[0108] [Table 8]

[0109]

[0110] In addition, based on the results of Test Examples 1 and 2, the concentrations of castor oil and polyvinyl alcohol, the weight ratio of castor oil to polyvinyl alcohol (C / P), and the relationship between the particle size change rate caused by autoclave sterilization and the change in properties relative to centrifugation are shown in Table 9.

[0111] [Table 9]

[0112]

[0113] *1 Particle size change before and after AC sterilization

[0114] *2 Changes in properties relative to centrifugation

[0115] *3 Weight ratio of castor oil to polyvinyl alcohol

[0116] *4 Example number or comparative example number

[0117] Emulsions containing 5-30% castor oil and 1-8% polyvinyl alcohol were evaluated for changes in particle size and properties after centrifugation due to autoclave sterilization (AC sterilization). Emulsions containing 5-20% castor oil and 2-7% polyvinyl alcohol showed good results. However, even with castor oil and polyvinyl alcohol within this range, unstable emulsions were obtained (Comparative Examples 19 and 21).

[0118] That is, it was clarified that only a formulation containing 5 to 20% castor oil and 2 to 7% polyvinyl alcohol, with a weight ratio of castor oil to polyvinyl alcohol of 1.25 to 5, is a stable oil-in-water emulsion.

[0119] (Test Example 3)

[0120] Oil-in-water emulsions were prepared according to the formulations shown in Tables 10 to 12. The preparation method was the same as in Test Example 1 (1-1). The properties of the crude emulsified emulsions were all "AA." The micronized oil-in-water emulsions were evaluated for changes in particle size due to autoclave sterilization (AC sterilization) and changes in properties relative to centrifugation using the methods of Test Examples 1 (1-2) and (1-3). The results are shown in Tables 10 to 12.

[0121] [Table 10]

[0122]

[0123] [Table 11]

[0124] g / 100mL Comparative Example 30 Comparative Example 31 Comparative Example 32 Comparative Example 33 coconut oil 20 - - - Squalane - 20 - - Oleyl alcohol - - 20 - Isopropyl myristate - - - 20 Polyvinyl alcohol (EG-05P) 4 4 4 4 concentrated glycerin 2.2 2.2 2.2 2.2 Sodium acetate hydrate 0.05 0.05 0.05 0.05 purified water appropriate amount appropriate amount appropriate amount appropriate amount pH 5.5 5.5 5.5 5.5 AC particle size before sterilization 168.3nm 182.0nm 288.4nm 346.4nm Particle size of AC after sterilization 174.0nm 206.2nm 618.3nm 807.7nm Particle size change rate of AC before and after sterilization 3.4％ 13.3％ 114.4％ 133.2％ Particle size changes caused by AC sterilization F F F F Changes in properties relative to centrifugation F F F F

[0125] [Table 12]

[0126]

[0127] As shown in Tables 10 to 12, changes in particle size and properties following centrifugation were evaluated for emulsions containing 20% ​​of various oil components and 4% polyvinyl alcohol. No favorable results were obtained for oil components other than castor oil. This demonstrates that only formulations containing castor oil as an oil component produce stable oil-in-water emulsions.

[0128] (Test Example 4)

[0129] Oil-in-water emulsions were prepared according to the formulation shown in Table 13. The preparation method was the same as in Test Example 1 (1-1). The properties of the crude emulsions were all "AA." The micronized oil-in-water emulsions were evaluated for changes in particle size due to autoclave sterilization (AC sterilization) and changes in properties relative to centrifugation using the methods of Test Examples 1 (1-2) and (1-3). The results are shown in Table 13.

[0130] [Table 13]

[0131]

[0132] *5Phase separation occurred and particle size could not be measured.

[0133] As shown in Table 13, emulsions containing 4% of hypromellose acetate succinate (AS-MF), polyethylene glycol graft copolymer (Soluplus), hypromellose phthalate (HP-50), polyoxyethylene hydrogenated castor oil (HCO-60), or polyoxyl 40 stearate were evaluated for changes in particle size and properties following centrifugation after autoclave sterilization (AC sterilization). Comparative Examples 36 to 40 all failed to produce favorable results. This demonstrates that only formulations containing polyvinyl alcohol as an emulsifier produce stable oil-in-water emulsions.

[0134] (Test Example 5) Freeze-thaw test

[0135] In the results of Test Example 1, freeze-thaw tests were conducted on the oil-in-water emulsion of Example 3, which showed the smallest change in particle size, and the oil-in-water emulsion of Comparative Example 21, which served as a comparison object. The oil-in-water emulsions filled in glass ampoules were transferred to a -30°C storage warehouse and frozen. The frozen oil-in-water emulsions were thawed at room temperature, and the post-thawing properties were observed. Emulsions that did not cream and were uniformly dispersed were rated "AA," those that creamed despite the oil phase not separating were rated "A," and those that separated into a transparent oil phase and a turbid aqueous phase were rated "F." The results are shown in Table 14.

[0136] [Table 14]

[0137]

[0138] As shown in Table 14, changes in properties in response to the freeze-thaw test were evaluated, and good results were obtained for the formulation in which the weight ratio of castor oil to polyvinyl alcohol was 5 or less.

[0139] Preparation Examples

[0140] According to the formulation shown in Table 15, the emulsion eye drops of Examples 8 to 10 were prepared by performing the same operation as in Test Example 1 (1-1) with the addition of a step of dissolving the drug in castor oil.

[0141] [Table 15]

[0142]

[0143] The embodiments and examples disclosed above should be considered in all respects as illustrative rather than restrictive. The scope of the present invention is not indicated by the embodiments and examples above, but by the claims, and includes all modifications and variations within the meaning and scope equivalent to the claims.

Claims

1. An emulsion eye drop comprising castor oil and polyvinyl alcohol, The concentration of castor oil is 5-10w / v%. The concentration of the polyvinyl alcohol is 2-4w / v%. The weight ratio of the castor oil to the polyvinyl alcohol is 1.2 to 5. The emulsion eye drops also contain a water-insoluble drug at a concentration of 0.001 to 2 w / v%, wherein the purified water required to dissolve 1 g at 25° C. and 1 atmosphere is 1000 ml or more. The emulsion eye drops do not contain a nonionic surfactant, Containing only the polyvinyl alcohol as a water-soluble polymer, When the emulsion eye drops are sterilized by autoclaving at 121° C. for 20 minutes, the change rate of the average particle size of oil droplets contained in the emulsion eye drops before and after the autoclave sterilization is less than 2%. Before the autoclave sterilization, the average particle size of the oil droplets contained in the emulsion eye drops is 100 to 200 nm. When the emulsion eye drops were centrifuged at 20,000×g for 20 minutes, the emulsion eye drops were homogeneous.

2. A method for stabilizing emulsion eye drops, comprising the steps of preparing the emulsion eye drops, wherein the emulsion eye drops contain castor oil and polyvinyl alcohol, The concentration of castor oil is 5-10w / v%. The concentration of the polyvinyl alcohol is 2-4w / v%. The weight ratio of the castor oil to the polyvinyl alcohol is 1.2 to 5. The emulsion eye drops also contain a water-insoluble drug at a concentration of 0.001 to 2 w / v%, which requires 1000 ml or more of purified water to dissolve 1 g at 25° C. and 1 atmosphere. The emulsion eye drops do not contain a nonionic surfactant, Containing only the polyvinyl alcohol as a water-soluble polymer, When the emulsion eye drops are sterilized by autoclaving at 121° C. for 20 minutes, the change rate of the average particle size of oil droplets contained in the emulsion eye drops before and after the autoclave sterilization is less than 2%. Before the autoclave sterilization, the average particle size of the oil droplets contained in the emulsion eye drops is 100 to 200 nm. When the emulsion eye drops were centrifuged at 20,000×g for 20 minutes, the emulsion eye drops were homogeneous.

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